Sex and interferon gamma signaling regulate microglia migration in the adult mouse cortex in vivo.

Although microglia possess the unique ability to migrate, whether mobility is evident in all microglia, is sex dependent, and what molecular mechanisms drive this, is not well understood in the adult brain. Using longitudinal in vivo two-photon imaging of sparsely labeled microglia, we find a relatively small population of microglia (~5%) are mobile under normal conditions. Following injury (microbleed), the fraction of mobile microglia increased in a sex-dependent manner, with male microglia migrating significantly greater distances toward the microbleed relative to their female counterparts. To understand the signaling pathways involved, we interrogated the role of interferon gamma (IFNγ). Our data show that in male mice, stimulating microglia with IFNγ promotes migration whereas inhibiting IFNγ receptor 1 signaling inhibits them. By contrast, female microglia were generally unaffected by these manipulations. These findings highlight the diversity of microglia migratory responses to injury, its dependence on sex and the signaling mechanisms that modulate this behavior.

MRI Imaging Appearance of Hyperostosis Frontalis Interna (HFI): A Case Report of Focal Benign Enhancement.

Hyperostosis frontalis interna (HFI) is a common and often incidental finding seen on imaging. There is a significant paucity of radiology literature, particularly regarding the MRI imaging appearance of HFI. We reported two cases of HFI on MRI, which showed focal enhancement. These were stable on long-term follow-up studies and thought to be most consistent with benign enhancement. Further studies are needed to elucidate the underlying pathogenesis; however, it is important to be aware that regions of HFI may demonstrate variable enhancement and are sometimes mistaken for osseous metastatic disease.

Effectiveness of High Power Laser Therapy on Pain and Isokinetic Peak Torque in Athletes with Proximal Hamstring Tendinopathy: A Randomized Trial.

Athletes such as long-distance runners, sprinters, hockey, and/or football players may have proximal hamstring tendinopathy (PHT). Laser therapy has been shown to be effective in tendinopathies. High power laser therapy (HPLT) is used for the treatment of several musculoskeletal conditions; however, its efficacy on PHT has not been investigated. This study is aimed at examining the effects of HPLT on pain and isokinetic peak torque (IPT) in athletes with PHT. The two-arm comparative pretest-posttest experimental design was used with random allocation of 36 athletes aged 18-35 years into two groups (experimental and conventional group). The experimental group included the application of HPLT for 3 weeks. The conventional group included treatment with a conventional physiotherapy program including ultrasound therapy, moist heat pack, and home exercises for a total of 3 weeks. Pain and IPT of the hamstring muscle were measured before and after the application of the intervention. Pain score decreased, and IPT increased significantly (p < 0.05) after application of HPLT, by 61.26% and 13.18%, respectively. In the conventional group, a significant difference (p < 0.05) was observed in pain scores only, which decreased by 41.14%. No significant difference (p > 0.05) was observed in IPT in the conventional group. When HPLT was compared with conventional physiotherapy, a significant difference was found in pain scores only. HPLT for 3 weeks was found to be effective in improving pain in athletes with PHT. However, no significant difference was found between HPLT and conventional physiotherapy (US, moist heat, and home exercises) in improving the IPT of the hamstring muscle.

Microvascular basis of cognitive impairment in type 1 diabetes.

The complex computations of the brain require a constant supply of blood flow to meet its immense metabolic needs. Perturbations in blood supply, even in the smallest vascular networks, can have a profound effect on neuronal function and cognition. Type 1 diabetes is a prevalent and insidious metabolic disorder that progressively and heterogeneously disrupts vascular signalling and function in the brain. As a result, it is associated with an array of adverse vascular changes such as impaired regulation of vascular tone, pathological neovascularization and vasoregression, capillary plugging and blood brain barrier disruption. In this review, we highlight the link between microvascular dysfunction and cognitive impairment that is commonly associated with type 1 diabetes, with the aim of synthesizing current knowledge in this field.

Fungal infections in hematopoietic stem-cell transplant patients: a review of epidemiology, diagnosis, and management.

The advent of bone marrow transplant has opened doors to a different approach and offered a new treatment modality for various hematopoietic stem-cell-related disorders. Since the first bone marrow transplant in 1957, there has been significant progress in managing patients who undergo bone marrow transplants. Plasma-cell disorders, lymphoproliferative disorders, and myelodysplastic syndrome are the most common indications for hematopoietic stem-cell transplant. Despite the advances, invasive fungal infections remain a significant cause of morbidity and mortality in this high-risk population. The overall incidence of invasive fungal infection in patients with hematopoietic stem-cell transplant is around 4%, but the mortality in patients with allogeneic stem-cell transplant is as high as 13% in one study. Type of stem-cell transplant, conditioning regimen, and development of graft-versus-host disease are some of the risk factors that impact the risk and outcomes in patients with invasive fungal infections. Aspergillus and candida remain the two most common organisms causing invasive fungal infections. Molecular diagnostic methods have replaced some traditional methods due to their simplicity of use and rapid turnaround time. Primary prophylaxis has undoubtedly shown to improve outcomes even though breakthrough infection rates remain high. The directed treatment has seen a significant shift from amphotericin B to itraconazole, voriconazole, and echinocandins, which have shown better efficacy and fewer adverse effects. In this comprehensive review, we aim to detail epidemiology, risk factors, diagnosis, and management, including prophylaxis, empiric and directed management of invasive fungal infections in patients with hematopoietic stem-cell transplant.

High fat diet and its effects on cognitive health: alterations of neuronal and vascular components of brain.

It has been well recognized that intake of diets rich in saturated fats could result in development of metabolic disorders such as type 2 diabetes mellitus, obesity and cardiovascular diseases. Recent studies have suggested that intake of high fat diet (HFD) is also associated with cognitive dysfunction. Various preclinical studies have demonstrated the impact of short and long term HFD feeding on the biochemical and behavioural alterations. This review summarizes studies and the protocols used to assess the impacts of HFD feeding on cognitive performance in rodents. Further, it discuss the key mechanisms that are altered by HFD feeding, such as, insulin resistance, oxidative stress, neuro-inflammation, transcriptional dysregulation and loss of synaptic plasticity. Along with these, HFD feeding also alters the vascular components of brain such as loss of BBB integrity and reduced cerebral blood flow. It is highly possible that these factors are responsible for the development of cognitive deficits as a result of HFD feeding.

The energetic brain - A review from students to students.

The past 20 years have resulted in unprecedented progress in understanding brain energy metabolism and its role in health and disease. In this review, which was initiated at the 14th International Society for Neurochemistry Advanced School, we address the basic concepts of brain energy metabolism and approach the question of why the brain has high energy expenditure. Our review illustrates that the vertebrate brain has a high need for energy because of the high number of neurons and the need to maintain a delicate interplay between energy metabolism, neurotransmission, and plasticity. Disturbances to the energetic balance, to mitochondria quality control or to glia-neuron metabolic interaction may lead to brain circuit malfunction or even severe disorders of the CNS. We cover neuronal energy consumption in neural transmission and basic ('housekeeping') cellular processes. Additionally, we describe the most common (glucose) and alternative sources of energy namely glutamate, lactate, ketone bodies, and medium chain fatty acids. We discuss the multifaceted role of non-neuronal cells in the transport of energy substrates from circulation (pericytes and astrocytes) and in the supply (astrocytes and microglia) and usage of different energy fuels. Finally, we address pathological consequences of disrupted energy homeostasis in the CNS.

Epigenetics in Neurodegenerative Diseases: The Role of Histone Deacetylases.

BACKGROUND & OBJECTIVE: Imbalance in histone acetylation levels and consequently the dysfunction in transcription are associated with a wide variety of neurodegenerative diseases. Histone proteins acetylation and deacetylation is carried out by two opposite acting enzymes, histone acetyltransferases and histone deacetylases (HDACs), respectively. In-vitro and in-vivo animal models of neurodegenerative diseases and post mortem brains of patients have been reported overexpressed level of HDACs. In recent past numerous studies have indicated that HDAC inhibitors (HDACIs) might be a promising class of therapeutic agents for treating these devastating diseases. HDACs being a part of repressive complexes, the outcome of their inhibition has been attributed to enhanced gene expression due to heightened histone acetylation. Beneficial effects of HDACIs has been explored both in preclinical and clinical studies of these diseases. Thus, their screening as future therapeutics for neurodegenerative diseases has been widely explored. CONCLUSION: In this review, we focus on the putative role of HDACs in neurodegeneration and further discuss their potential as a new therapeutic avenue for treating neurodegenerative diseases.

A preliminary report on physical activity patterns among children aged 8-14 years to predict risk of cardiovascular diseases in Malwa region of Punjab.

OBJECTIVE: To determine the pattern of physical activity specific to age and gender among young Indian school going girls and boys aged 8-14 years. DESIGN: Cross-sectional study. SETTING: Private and government sponsored schools in Patiala and Mansa District of Punjab, India. PARTICIPANTS: Two hundred thirty four school going girls and boys aged 8-14 years. METHODOLOGY: A structured questionnaire recorded the various forms of daily physical activity, sedentary activity as well as physical activity level of all the participants. The energy expenditure was also calculated using the standard metabolic equivalent index. RESULTS: There is a significant difference between mean weights of participants belonging to different physical activity levels (p<.04). In comparison to boys, the girl participants have significant lower values of physical activity duration as well as total metabolic equivalent expenditure (p<.05). The total duration of moderate/vigorous physical activity declined in both girls and boys as the age increased. CONCLUSION: Physical activity among children in Northern regions of India is on decline as their age increases especially among girls. It is important to determine physical activity duration in early age groups and motivate children for daily physical activity.

High fat diet feeding induced insulin resistance exacerbates 6-OHDA mediated neurotoxicity and behavioral abnormalities in rats.

Some of the clinical reports suggest that insulin resistance could be a risk factor for Parkinson's disease (PD) development, however experimental data is scarce. Our previous work has suggested that insulin resistance could be an important factor that leads to diabetes associated neurodegeneration. In the present study, we evaluated whether insulin resistance is linked to PD pathology or not. For this purpose, we first standardized an animal model which could mimic the co-morbid insulin resistance and PD condition. For development of insulin resistance, we fed the male Wistar rats with high fat diet (HFD) for eight weeks, followed by 6-hydroxydopamine (6-OHDA) administration, a toxin widely used for PD induction, in medial forebrain bundle (MFB) of rats. The 6-OHDA treatment resulted in neuronal damage and loss of striatal dopamine level. This dopamine loss was correlated with impaired performance in behavioral tasks such as rotarod, narrow beam walk test and locomotor activity. Interestingly, we found that exposure to HFD exacerbated the effects of 6-OHDA on striatal dopamine loss and behavioral parameters in rats, indicating that HFD-induced insulin resistance is associated with a diminished capacity of dopaminergic neurons to cope with 6-OHDA mediated neurotoxicity. Based upon these findings, it can be suggested that HFD feeding induced insulin resistance exacerbates the PD pathology.

Efficacy of Osteopathic Manipulative Treatment Approach in the Patient with Pulmonary Fibrosis in Critical Care Outpatient Department.

The purpose of the present case study was to explore the efficacy of osteopathic manipulative treatment (OMT) in patient with pulmonary fibrosis (PF) in the critical care outpatient department. Here, we present a 48-year-old male case with breathlessness, increased frequency of defecation, and pain in and around the nape of neck with diagnosed pulmonary fibrosis. He scored 3 on a patient-reported modified Medical Research Council (mMRC) dyspnea scale. Osteopathic examination reveals multiple somatic findings across the chest and abdominal region and treated by OMT. Pre- and post-intervention changes were assessed by the 13-item shortness of breath with daily activities (13iSOBDA). 27.2, 22, 16.4, and 11.8 were noted at the end of 1st, 2nd, 3rd, and 4th week of intervention, respectively, on 13iSOBDA while mMRC decreased from 3 to 1. OMT may be a feasible option in decreasing the symptoms of the PPF in the critical care outpatient department.

The effectiveness of osteopathic manipulative treatment in an abnormal uterine bleeding related pain and health related quality of life (HR-QoL) - A case report.

Abnormal uterine bleeding is characterized by painful and/or excessive menorrhea, chronic pelvic pain due to the endometriosis (Em). Osteopathic treatment is commonly used in the gynecological dysfunctions. The aim of the present case study was to explore the effect of osteopathic treatment (OT) for a woman with abnormal uterine bleeding related pain and quality of life (QoL). We reported a case of 29 year old female who presented with chief complaints of increased flow during periods, lower abdominal pain, leukorrhoea, lower back pain and with occasional constipation for the last 3 years. Patient is a mother of 6 years old male child born with normal delivery. On diagnostic ultrasonography the uterus was found bulky with insignificant endometriosis and no other abnormality was detected. She did not have any relevant past medical and surgical history. The pre and post osteopathic treatment measurements were measured using Visual Analog Scale (VAS) and the health related quality of life (HR-QoL) questionnaire called short form Endometriosis Health Profile Questionnaire (EHP) - 5. In the present case the pain due to the endometriosis was treated with the osteopathic treatment consists of all the major diaphragms' release (release of pelvic diaphragm, abdominal diaphragm, thoracic outlet release and hyoid diaphragm) during the first session and in the second session gastro-esophageal (GE) junction release, sigmoid colon release, cranial therapy to the occiput, sacral release and dural tube rocking. Following that improvement of pain from VAS 8.3/10 to 3.9/10 and QoL improvement from EHP-5, 72/100 to 26/100 was noted. Osteopathic manipulative approach (OMA) in the patient with Em might improve the abnormal uterine bleeding related pain and health related quality of life (HR-QoL).

The malleable brain: plasticity of neural circuits and behavior - a review from students to students.

One of the most intriguing features of the brain is its ability to be malleable, allowing it to adapt continually to changes in the environment. Specific neuronal activity patterns drive long-lasting increases or decreases in the strength of synaptic connections, referred to as long-term potentiation and long-term depression, respectively. Such phenomena have been described in a variety of model organisms, which are used to study molecular, structural, and functional aspects of synaptic plasticity. This review originated from the first International Society for Neurochemistry (ISN) and Journal of Neurochemistry (JNC) Flagship School held in Alpbach, Austria (Sep 2016), and will use its curriculum and discussions as a framework to review some of the current knowledge in the field of synaptic plasticity. First, we describe the role of plasticity during development and the persistent changes of neural circuitry occurring when sensory input is altered during critical developmental stages. We then outline the signaling cascades resulting in the synthesis of new plasticity-related proteins, which ultimately enable sustained changes in synaptic strength. Going beyond the traditional understanding of synaptic plasticity conceptualized by long-term potentiation and long-term depression, we discuss system-wide modifications and recently unveiled homeostatic mechanisms, such as synaptic scaling. Finally, we describe the neural circuits and synaptic plasticity mechanisms driving associative memory and motor learning. Evidence summarized in this review provides a current view of synaptic plasticity in its various forms, offers new insights into the underlying mechanisms and behavioral relevance, and provides directions for future research in the field of synaptic plasticity. Read the Editorial Highlight for this article on page 788. Cover Image for this issue: doi: 10.1111/jnc.13815.

The strain - Counter strain technique in the management of anterior interosseous nerve syndrome: A case report.

Anterior interosseous nerve syndrome (AINS) is a proximal median nerve neuropathy affecting the forearm. Trigger points in the anterior compartment of the forearm may cause compression of the anterior interosseous nerve (AIN) which, in turn, may result in muscle weakness. Here we present the case of a 37-year-old female who complained of an abnormal pen grip while writing. Clinical examination (observation, palpation, pincer grip strength) showed weak pincer grip strength, an active trigger point in the middle of the anterior forearm and a positive circle sign. Her treatment course included cryomassage, neural mobilization, transcutaneous electrical nerve stimulation (TENS) and the strain-counter strain (SCS) technique four times a week for two weeks. On follow-up, the patient reported an inactive trigger point on palpation, improvement in her handwriting and improved pincer (fingertip pinch) grip strength in pounds (lbs) as recorded by the Baseline Hydraulic Pinch Gauge. This case report explored the effectiveness of SCS as an important adjunct to other conservative treatments for entrapment neuropathies. SCS has also shown its potential to improve muscle strength.

Histone deacetylase inhibitors: Future therapeutics for insulin resistance and type 2 diabetes.

Insulin resistance is a common feature of obesity and predisposes the affected individuals to a variety of pathologies, including type 2 diabetes mellitus (T2DM), dyslipidemias, hypertension, cardiovascular disease etc. Insulin resistance is the primary cause of T2DM and it occurs many years before the disease onset. Although Thiazolidinediones (TZDs) such as rosiglitazone and pioglitazone are outstanding insulin sensitizers and are in clinical use since 1990s, however, their serious side effects such as heart attack and bladder cancer have limited their utilization. Thus, there is an unmet need to identify a new class of drugs with insulin sensitizing activity and minimal side effects. In the recent years, Histone deacetylase (HDAC) has emerged as a new molecular target in the control of insulin resistance and T2DM. The level of histone acetylation/deacetylation has been found to be altered during insulin resistance and T2DM conditions. HDAC inhibitors have been found to effectively manage insulin resistance and T2DM in various preclinical models and clinical trials. In this review we will focus on various aspects related to regulation of insulin signalling by HDACs and the future scope of HDAC inhibitors as therapeutics for insulin resistance.

The California Tri-pull Taping Method in the Treatment of Shoulder Subluxation After Stroke: A Randomized Clinical Trial.

BACKGROUND: Shoulder subluxation is a frequent occurrence in individuals following a stroke. Although various methods of treatment are available, none of them address all possible consequences of the subluxation pain, limited range of motion, the subluxation, and decreased functional use of the arm. AIMS: The purpose of this study was to evaluate the effectiveness of California tri-pull taping (CTPT) method on shoulder subluxation, pain, active shoulder flexion, and upper limb functional recovery after stroke. MATERIALS AND METHODS: This was a randomized control study on 30 participants. All participants received conventional neurorehabilitation 5 days a week over 6 weeks. Half of the participants also received the CTPT. Pre- and post-assessment scores were taken on all participants for the amount of shoulder subluxation, pain, active shoulder flexion, and functional recovery. RESULTS: The CTPT method demonstrated a significant reduction of pain in the treatment group from baseline, a significant improvement in active shoulder flexion and a significant improvement in proximal arm function as measured on the proximal subscale on the Fugl-Meyer upper extremity functional Scale but not the distal or total Fugl-Meyer subscales. Shoulder subluxation was not statistically significant. CONCLUSIONS: The CTPT method is an effective treatment for the hemiplegic subluxed shoulder.

Epigenetic modifications by inhibiting histone deacetylases reverse memory impairment in insulin resistance induced cognitive deficit in mice.

Insulin resistance has been reported as a strong risk factor for Alzheimer's disease. However the molecular mechanisms of association between these still remain elusive. Various studies have highlighted the involvement of histone deacetylases (HDACs) in insulin resistance and cognitive deficits. Thus, the present study was designed to investigate the possible neuroprotective role of HDAC inhibitor, suberoylanilide hydroxamic acid (SAHA) in insulin resistance induced cognitive impairment in mice. Mice were subjected to either normal pellet diet (NPD) or high fat diet (HFD) for 8 weeks. HFD fed mice were treated with SAHA at 25 and 50 mg/kg i.p. once daily for 2 weeks. Serum insulin, glucose, triglycerides, total cholesterol and HDL-cholesterol levels were measured. A battery of behavioral parameters was performed to assess cognitive functions. Level of tumour necrosis factor (TNF-α) was measured in hippocampus to assess neuroinflammation. To further explore the molecular mechanisms we measured the histone H3 acetylation and brain derived neurotrophic factor (BDNF) level. HFD fed mice exhibit characteristic features of insulin resistance. These mice also showed a severe deficit in learning and memory along with reduced histone H3 acetylation and BDNF levels. In contrast, the mice treated with SAHA showed significant and dose dependent improvement in insulin resistant condition. These mice also showed improved learning and memory performance. SAHA treatment ameliorates the HFD induced reduction in histone H3 acetylation and BDNF levels. Based upon these results, it could be suggested that HDAC inhibitors exert neuroprotective effects by increasing H3 acetylation and subsequently BDNF level.

Transcriptional dysregulation in Huntington's disease: The role of histone deacetylases.

Huntington's disease (HD) is a progressive neurological disorder for which there are no disease-modifying treatments. Although, the exact underlying mechanism(s) leading to the neural cell death in HD still remains elusive, the transcriptional dysregulation is a major molecular feature. Recently, the transcriptional activation and repression regulated by chromatin acetylation has been found to be impaired in HD pathology. The acetylation and deacetylation of histone proteins is carried out by opposing actions of histone acetyl-transferases and histone deacetylases (HDACs), respectively. Studies carried out in cell culture, yeast, Drosophila and rodent model(s) have indicated that HDAC inhibitors (HDACIs) might provide useful class of therapeutic agents for HD. Clinical trials have also reported the beneficial effects of HDACIs in patients suffering from HD. Therefore, the development of HDACIs as therapeutics for HD has been vigorously pursued. In this review, we highlight and summarize the putative role of HDACs in HD like pathology and further discuss the potential of HDACIs as new therapeutic avenues for the treatment of HD.

Beneficial effects of sodium butyrate in 6-OHDA induced neurotoxicity and behavioral abnormalities: Modulation of histone deacetylase activity.

Parkinson's disease (PD) is the second most common neurodegenerative disorder. Recent studies have investigated the involvement of epigenetic modifications in PD. Histone deacetylase (HDAC) inhibitors have been reported to be beneficial in cognitive and motor deficit states. The present study was designed to investigate the effect of sodium butyrate, a HDAC inhibitor in 6-hydroxydopamine (6-OHDA) - induced experimental PD like symptoms in rats. To produce motor deficit, 6-OHDA was administered unilaterally in the right medial forebrain bundle. Three weeks after 6-OHDA administration, the rats were challenged with apomorphine. Following this, the animals were treated with sodium butyrate (150 and 300 mg/kg i.p.) once daily for 14 days. Movement abnormalities were assessed by battery of behavioral tests. Biochemically, oxidative stress markers, neuroinflammation and dopamine were measured in striatal brain homogenate. Further, to explore the molecular mechanism(s), we measured the level of global H3 histone acetylation and brain derived neurotrophic factor (BDNF). 6-OHDA administration results in significant motor deficit along with reduction in striatal dopamine level. 6-OHDA treated rats showed elevated oxidative stress and neuroinflammatory markers. Treatment with sodium butyrate results in significant attenuation of motor deficits and increased striatal dopamine level. Moreover, sodium butyrate treatment attenuated the oxidative stress and neuroinflammatory markers. These effects occur concurrently with increased global H3 histone acetylation and BDNF levels. Thus, the observed results of the present study are indicative for the therapeutic potential of HDAC inhibitors in PD.

Targeting histone deacetylases: a novel approach in Parkinson's disease.

The worldwide prevalence of movement disorders is increasing day by day. Parkinson's disease (PD) is the most common movement disorder. In general, the clinical manifestations of PD result from dysfunction of the basal ganglia. Although the exact underlying mechanisms leading to neural cell death in this disease remains unknown, the genetic causes are often established. Indeed, it is becoming increasingly evident that chromatin acetylation status can be impaired during the neurological disease conditions. The acetylation and deacetylation of histone proteins are carried out by opposing actions of histone acetyltransferases (HATs) and histone deacetylases (HDACs), respectively. In the recent past, studies with HDAC inhibitors result in beneficial effects in both in vivo and in vitro models of PD. Various clinical trials have also been initiated to investigate the possible therapeutic potential of HDAC inhibitors in patients suffering from PD. The possible mechanisms assigned for these neuroprotective actions of HDAC inhibitors involve transcriptional activation of neuronal survival genes and maintenance of histone acetylation homeostasis, both of which have been shown to be dysregulated in PD. In this review, the authors have discussed the putative role of HDAC inhibitors in PD and associated abnormalities and suggest new directions for future research in PD.